As previously, the planned studies in this request are directed to clarification of the interrelationships between hormones and various circulating and stored metabolites in man, where feasible, and otherwise in experimental animals. Since insulin appears to be the hormone primarily involved in fuel homeostasis (and probably to a lesser degree, glucagon), its role in controlling substrate levels such as amino acids in blood and tissues in different metabolic states will continue to be the main focus. Previously we have been principally involved in characterization of the prolonged fasted state, and now are directing attention to the steady-states achieved in high and low carbohydrate infusions or ingestion, amino acid infusion or protein ingestion, in states associated with suppression of endogenous insulin and glucagon by somatostatin infusion, and then returning one or the other of these two hormones to normal in certain states such as that achieved in the fasted overweight juvenile-diabetic on long-acting insulin preparations, and in certain other pathological states such as in uremia. In each of these, regional metabolism like that across the forearm or splanchnic bed will be characterized, and special emphasis will be directed to the kidney, both in normal and pathological states. The integration of this information should provide knowledge as to how insulin, glucagon, growth hormone, adrenal corticoids and other factors interrelate in normal physiology, in diabetes, and in uremia, and how they contribute to the pathology of these diseases. Other studies relate to the phylogeny of fuel homeostasis, to certain specific metabolic disorders like tumor hypoglycemia or lipoatrophic diabetes and to some limited studies into reactions involving the beta cell and its response to chemical toxins.